Ubiquitin and Protein Degradation in Synapse Function

Abstract

The remodeling of synapses is a fundamental mechanism for information storage and processing in the brain. During brain development, and in response to learningrelated activity, synapses undergo remarkable structural changes, including growth, shrinkage, and elimination. Such structural plasticity provides a physical basis for enduring changes in neural circuits that are mediated by alterations in the molecular composition of the synapse. Indeed, stabilization or removal of neurotransmitter receptors, scaffold proteins, and signaling molecules from the synapse has been proposed to account for long-term changes in synaptic strength. Patterns of molecular changes in large sets of synaptic proteins, which ultimately encode the history of activity at the synapse, represent a level of complexity that we are only now beginning to understand. Long-lasting changes in the molecular content of synapses arise by two general mechanisms: the incorporation of new proteins and the selective removal of existing synaptic proteins. For much of the past two decades, the prevailing model for enduring changes in synapse function and structure has been stimulus-dependent gene expression and protein synthesis. Indeed, substantial evidence indicates that transcriptional events are critical for long-term activity-dependent plasticity (135, 184). In addition, local translation of mRNAs is thought to orchestrate long-lasting forms of learning-related synaptic plasticity (269). On the other hand, considerably less attention has been given to the contribution of protein turnover to long-term structural and functional changes at synapses. What controls the turnover and replacement of synaptic proteins? For most cellular proteins, the major pathway of degradation occurs by ubiquitin conjugation and subsequent targeting of ubiquitin-conjugated proteins to the proteasome. Here we will discuss the role of the ubiquitin–proteasome system (UPS) in the structural and